05). The differences in biomarker values PI3K inhibitor between the 2 groups are listed in Table 2. The levels of the bone formation markers serum OC and serum BAP, and those of the bone degradation markers urine DPD, urine NTX, and serum CTX were not significantly different between the 2 groups; only levels of serum PTH showed a significant difference (P < 0.05). Regarding the serum total calcium and albumin-adjusted total calcium, the

values in BRONJ group (n = 29; 8.85 ± 0.47 and 9.09 ± 0.84, respectively) were significantly lower than that of Non-BRONJ group (n = 24; 9.36 ± 0.51 and 9.50 ± 0.45, respectively) (P < 0.05). The serum CTX level in reference to a 150 pg/mL cutoff was also not significant for the development

of BRONJ (P > 0.05). When considering the daily trend of biomarker levels (for OC, DPD, CTX, and NTX) after BP discontinuation in BRONJ patients, the mixed model analysis with repeated measures revealed no time trends for OC (estimated regression coefficient [β] = 0.031, 95% CI − 0.001 to 0.063, P = 0.057), DPD (β = 0.004, 95% CI − 0.028 to 0.020, P = 0.745), and NTX (β = 0.153, 95% CI − 0.036 to 0.342, P = 0.110), with the exception of CTX (β = 0.002, 95% CI 0.000 to 0.003, P = 0.007) ( Fig. 1). That is, the CTX levels of BRONJ patients increased by 2 pg/mL per day from the baseline mean of 177 pg/mL after BP discontinuation. In the ROC Inhibitor high throughput screening curve analysis for PTH, which was a significant biomarker, the AUC was 0.719 (95% CI 0.556–0.882, P = 0.009) ( Fig. 2). The cutoff value with both maximal sensitivity and specificity was > 41.52 pg/mL. At this cutoff, the sensitivity and specificity of PTH for

the prediction of BRONJ development was 56.5% and 86.7%, respectively. For CTX, the AUC was 0.619 (95% CI 0.499–0.730, P = 0.069) and the cutoff value was ≤ 0.094 ng/mL (sensitivity, 29.7%; specificity, 89.2%). When 150 pg/mL was set as the standard, the sensitivity was 54.1% and the specificity was 35.1%. This study was conducted to investigate the possible associations of the bone biomarkers OC, CTX, NTX, DPD, BAP, and PTH as risk predictors of BRONJ. Thus, a case–control study involving patients with a diagnosis of BRONJ and an age- and gender-matched Pyruvate dehydrogenase control group was conducted. This study was important in that it was an investigation of controversial bone biomarkers involving a relatively large BRONJ patient sample size, at a single institution with a single standard for BRONJ diagnosis criteria and sampling protocols. BPs are most often used in the nonhormonal treatment of osteoporosis and are also widely used for cancer metastasis and various bone diseases. Their use has been increasing steadily, and the associated incidence of BRONJ is also increasing [18].